Yuko Kanbayashi

Statistical identification of predictors for peripheral neuropathy associated with administration of bortezomib, taxanes, oxaliplatin or vincristine using ordered logistic regression analysis.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major drug-induced adverse reaction that becomes a dose-limiting toxicity. However, effective strategies for preventing or treating CIPN are lacking. Accordingly, this study aimed to statistically identify predictors for CIPN. Retrospective analysis was carried out for 190 patients who had been treated with bortezomib (n=28), taxanes (paclitaxel or docetaxel; n=58), oxaliplatin (n=52) or vincristine (n=52) at our hospital between April 2005 and December 2008. The severity of CIPN was assessed at the time of chemotherapy completion, graded as grade 0–5 in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Multivariate ordered logistic regression analysis was used to investigate predictors for CIPN. Predictors for CIPN in patients that were administered bortezomib were no co-administration of dexamethasone [odds ratio (OR), 0.455; confidence interval (CI), 0.208–0.955; P=0.0376] and sex (male) (OR, 3.035; CI, 1.356–6.793; P=0.0069). For taxanes (paclitaxel or docetaxel), the predictor for CIPN was a large number of chemotherapy cycles (OR, 2.379; CI, 1.035–5.466; P=0.0412). For oxaliplatin, the predictors for CIPN were a large number of chemotherapy cycles (OR, 3.089; CI, 1.598–5.972; P=0.0008) and no co-administration of non-steroidal anti-inflammatory drugs (OR, 0.393; CI, 0.197–0.785; P=0.0082). For vincristine, predictors for CIPN were a large number of chemotherapy cycles (OR, 6.015; CI, 1.880–19.248; P=0.0025) and co-administration of an analgesic adjuvant (OR, 3.907; CI, 1.383–11.031; P=0.0101). In conclusion, our study indicates that CIPN will be alleviated by the co-administration of dexamethasone with bortezomib and non-steroidal anti-inflammatory drugs with oxaliplatin.

Risk factors for infection in haematology patients treated with rituximab

Objectives:  Although rituximab therapy is not considered to be closely associated with infection, there have been reports of serious infections in patients treated with rituximab. We performed a statistical retrospective analysis to clarify the risk factors for infection in patients receiving rituximab therapy.

Predictive factors for postherpetic neuralgia using ordered logistic regression analysis.

Objectives:To identify predictive factors for the occurrence of postherpetic neuralgia (PHN). Methods:The participants were 73 herpes zoster patients who had been treated at the pain clinic of our hospital between January 2008 and June 2010. Variables present at the initial visit were extracted from the clinical records for regression analysis of factors related to the occurrence of PHN. The following scores for response were used: 0=no PHN after 3 months; 1=PHN present after 3 months but absent after 6 months; and 2=PHN present after 6 months. Multivariate ordered logistic regression analysis was performed to identify the predictive factors for PHN. Results:Advanced age [odds ratio (OR)=2.740, confidence interval (CI)=1.110-6.761; P=0.0288] and deep pain (OR=4.244, CI=1.114-16.163; P=0.0341) at the initial visit to our outpatient pain clinic were found to be significant predictive factors for the occurrence of PHN. Diabetes mellitus (OR=3.075) and pain reduced by bathing (OR=3.389) also had high OR, although they were not significant. Discussion:Our study indicates that advanced age and deep pain at the initial visit are significant predictors for PHN. Our results are considered likely to contribute to the establishment of evidence-based medicine in the optimal treatment of PHN.

Factors predicting requirement of high-dose transdermal fentanyl in opioid switching from oral morphine or oxycodone in patients with cancer pain.

ObjectivesTo identify predictive factors requiring high-dose transdermal fentanyl in opioid switching from oral morphine or oxycodone to transdermal fentanyl in patients with cancer pain. MethodsThe participants were 76 hospitalized terminal cancer patients who underwent opioid switching from oxycodone or morphine sustained-release tablet to transdermal fentanyl at our hospital between January 2009 and June 2010. The conversion dose was calculated as transdermal fentanyl (25 &mgr;g/h)/oral morphine (60 mg) or oxycodone (40 mg)=1. The response evaluated was the dose conversion ratio [transdermal fentanyl/oral morphine or oxycodone (conversion dose to fentanyl)]=Y and was taken to be 0 for Y⩽1, 1 for 1<Y⩽2, 2 for 2<Y⩽3, and 3 for 3<Y. Predictors evaluated were factors potentially impacting pain. Ordered logistic regression analysis was carried out to identify the predictive factors requiring high-dose transdermal fentanyl in opioid switching. ResultsBreast cancer [odds ratio (OR)=8.218; 95% confidence interval (CI), 1.219-55.407; P=0.0305], total protein level (OR=0.630; 95% CI, 0.408-0.974; P=0.0377), alanine aminotransferase level (OR=1.017; 95% CI, 1.001-1.033; P=0.0390), advanced age (OR=3.700; 95% CI, 1.360-10.063; P=0.0104), and male sex (OR=3.702; 95% CI, 1.355-10.115; P=0.0107) were found to be significant predictive factors requiring high-dose transdermal fentanyl in opioid switching. DiscussionOur study indicates that breast cancer, total protein, alanine aminotransferase, advanced age, and male sex are significant predictors of a need for higher dose transdermal fentanyl in opioid switching. Our results are considered likely to contribute to the establishment of evidence-based medicine in pain relief and palliative care.

Optimized dosage and frequency of cefozopran for patients with febrile neutropenia based on population pharmacokinetic and pharmacodynamic analysis

OBJECTIVES To establish a cefozopran (a fourth-generation cephem) population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria. METHODS We conducted a prospective clinical trial of cefozopran for haematological patients with febrile neutropenia (FN). Twenty-two patients (30 episodes) were selected to receive intravenous cefozopran every 8 h on a daily basis. We gathered concentration data and performed the NONMEM program. The Monte Carlo simulation was performed to assess the pharmacodynamic exposure based on the population pharmacokinetics and MIC. RESULTS The NONMEM program demonstrated that a two-compartment model provided a best fit for the data, that is, CL of 4.62 (L/h), V1 of 10.3 (L), Q of 4.47 (L/h), and V2 of 4.48 (L). On the basis of the Japanese national surveillance findings for Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus, viridans group streptococci, Escherichia coli and Klebsiella pneumoniae, Monte Carlo simulation data showed that probability of target attainment(T>MIC = 70%) is 67% to 97% for dosing every 8 h, and 48% to 88% for dosing every 12 h. For the patients in whom the efficacy of cefozopran could be evaluated, 17 of 22 patients (77.2%) survived the episode of FN without requiring further antibacterial treatment. CONCLUSIONS Our study proved that Monte Carlo simulation based on population pharmacokinetics can determine optimized dosage and method. The optimal regimen for this cephem was found to be three times daily.

Population pharmacokinetics of itraconazole solution used as prophylaxis for febrile neutropenia

Although administration of antifungal agents, such as itraconazole (ITC) solution, for prophylaxis is the most promising strategy for the treatment of haematological malignancies, little is known about the population pharmacokinetic (PK) parameters. A clinical study was conducted to identify PK parameters for the administration of 200mg/day ITC solution used as prophylaxis for febrile neutropenia in patients undergoing treatment. The study population comprised six patients. NONMEM software was used to estimate PK parameters. Clearance, volume of distribution and the absorption rate constant were 12.7 L/h, 333 L and 1.72 h(-1), respectively. These parameters were different from a previous study to large extent, which may be due to differences in intended patients. These differences strongly suggest that establishment of population pharmacokinetics is essential for planning a prospective clinical trial. Assuming a normal distribution, we predicted the trough concentrations of 94.5% of the patients receiving 200 mg/day ITC solution to be >250 ng/mL, indicating that administration of 200mg/day might be suitable for prophylaxis. This pilot study presents a basic PK model of ITC solution in Japanese haematological patients for the establishment of optimal administration. Large-scale studies will be necessary in the future to determine population PK parameters with covariates.

Statistical validation of the relationships of cancer pain relief with various factors using ordered logistic regression analysis.

Objective To clarify the relationships of cancer pain with various factors that prevent pain control statistically. Methods The participants were 71 terminal cancer patients admitted to the Department of Hematology/Oncology or Department of Gastroenterology/Hepatology, University Hospital, Kyoto Prefectural University of Medicine in whose pain control a pharmacist was involved as part of her clinical duties from January 2004 to November 2006. The effectiveness of pain control was evaluated using a 5-point verbal rating scale (0=excellent, 1=good, 2=moderate, 3=poor, and 4=very poor) by interviewing the patients. As pain was rated using a graded scale and as many factors were involved in pain, analysis was performed using ordered logistic regression analysis. Moreover, prediction of an optimal model was performed by leave-one-out cross-validation to eliminate unnecessary variables. A program to perform leave-one-out cross-validation by ordered logistic regression analysis was prepared, independent variables used in the model were increased one by one, and calculation was performed in all combinations. Then, the optimal model was predicted by calculating the percent accuracy of predictions and Spearman rank correlation coefficient. Results Nausea [odds ratio (OR)=1.948, P=0.0232], sex (OR=2.322, P=0.0030), and bone metastasis (OR=2.367, P=0.0017) remained as variables significantly correlated with pain when the number of independent variables was 5, and sex (OR=2.167, P=0.006) and bone metastasis (OR=2.093, P=0.005) remained when the number of variables was 6. Discussion The statistical identification of factors preventing pain control is considered to contribute to the establishment of an evidence-based approach to cancer pain relief.

Factors predicting adverse events associated with pregabalin administered for neuropathic pain relief

Pregabalin is an anticonvulsant drug that has been demonstrated to be effective in the treatment of neuropathic pain; however, data have indicated that the use of this drug is associated with adverse events, the frequency of which may vary according to the indication for which it is used. This retrospective study included 208 patients with neuropathic pain treated with pregabalin whose medical records were analyzed to identify factors associated with the occurrence of adverse events.

Predictive Factors for Postherpetic Neuralgia and Recent Pharmacotherapies

Postherpetic neuralgia (PHN) is a form of refractory chronic neuralgia that, despite the importance of prevention, currently lacks any effective prophylaxis. The efficacy of live zoster vaccine in preventing PHN was recently reported [1]. However, this vaccine appeared to be of limited use in prophylaxis[2]. PHN has a variety of symptoms and significantly affects patient quality of life [3-12]. Various studies have statistically analyzed predictive factors for PHN [13-23], but neither obvious pathogenesis nor established treatment has been clarified or established. We designed and conducted a study on the premise that statistical identifica‐ tion of significant predictors for PHN would contribute to the establishment of an evidencebased medicine approach to the optimal treatment of PHN. As a result, we reported our paper “Predictive Factors for Postherpetic Neuralgia Using Ordered Logistic Regression Analysis” [24].

Predictive Factors for Agitation Severity of Hyperactive Delirium in Terminally Ill Cancer Patients in a General Hospital Using Ordered Logistic Regression Analysis

BACKGROUND Despite the fact that many cancer patients worldwide die in general hospitals, there are few reports of the analysis of delirium in terminally ill cancer patients in this setting. PURPOSE This study aimed to identify predictive factors for agitation severity of hyperactive delirium in terminally ill cancer patients in a general hospital. METHODS Participants were 182 consecutively admitted terminally ill cancer patients who died in a Japanese general hospital between April 2009 and March 2011. Variables present one week before death were extracted from the clinical records for regression analysis of factors potentially related to agitation severity of delirium. The prevalence and agitation severity of delirium were evaluated retrospectively. Multivariate ordered logistic regression analysis was performed to identify predictive factors. RESULTS Male sex [odds ratio (OR)=2.125, 95% confidence interval (CI)=1.111-4.067; P=0.0227]; total bilirubin (T-bil) [OR=1.557, CI=1.082-2.239; P=0.017]; antibiotics [OR=0.450, CI=0.219-0.925; P=0.0298]; nonsteroidal antiinflammatory drugs (NSAIDs) [OR=2.608, CI=1.374-4.950; P=0.0034]; and hematological malignancy [OR=3.903, CI=1.363-11.179; P=0.0112] were found to be statistically significant predictors for agitation severity of hyperactive delirium. CONCLUSIONS Our study indicates that male sex, T-bil, antibiotic therapy, NSAID therapy, and hematological malignancy are significant predictors for agitation severity of hyperactive delirium in terminally ill cancer patients in a general hospital setting.